Adult thyroid is considered not to regenerate, however, it can regenerate and undergo folliculogenesis when necessary such as after damages due to exposure to radiation and/or chemicals. How this occurs remains unknown. In order to address this question, we used Nkx2-1(fl/fl);TPO-cre mouse that was produced in our laboratory. NKX2-1 is one of the thyroid and lung differentiation markers and the critical transcription factor, which regulates development, homeostasis, and function of thyroid and lung. The Nkx2-1(fl/fl);TPO-cre mice have the Nkx2-1 gene disrupted in their thyroid follicular cells in a hypomorphic fashion; the thyroid follicles consist of follicular cells that have the Nkx2-1 gene almost completely disrupted, while other follicles have no alterations in the Nkx2-1 gene expression levels. As a result, their thyroids appear to have approximately a half of the Nkx2-1 genes deleted. The Nkx2-1(fl/fl);TPO-cre mice thyroids are very disorganized and the follicular cells having lost the NKX2-1 expression appear to undergo degeneration. This leads to approximately a 2-fold higher proliferation rate, which contributes to a higher incidence of thyroid tumors induced by genotoxic carcinogen such as N-bis(2-hydroxypropyl)-nitrosamine (DHPN). Thus the thyroids of these mice possess the condition under constant degeneration and regeneration, which provides a good model to study thyroid regeneration. In the thyroids of Nkx2-1(fl/fl);TPO-cre mice, a zone of possible precursor cells to thyroid follicular cells were detected aligning near the tracheal cartilage and muscle which are thinner and elongated in shape as compared with round shape follicular cells. NKX2-1 expression was found in these elongated cells, suggesting that they are in thyroid lineage. A newly formed follicle-like structure was found connected at the end or in the middle of the zone of elongated cells. When bone marrow cells derived from GFP-transgenic mice were administered to the Nkx2-1(fl/fl);TPO-cre mice in transplant experiments, some GFP-positive cells were found surrounding NKX-2-1-positive cells in the zone of elongated cells. The results suggest that a zone of clustered cells could be, at least partly, derived from bone marrow cells. We propose a mechanism for thyroid regeneration that a cluster of elongated NKX2-1-positive cells near the tracheal cartilage and muscle may be precursor cells that mature to become thyroid follicular cells, and to form thyroid follicles. Understanding the mechanism of thyroid regeneration is critical for understanding the nature of thyroid stem/progenitor cells and their roles in this process and thyroid carcinogenesis. As part of the study, we have focused on the insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid. These signaling are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) for proliferation of thyroid follicular cells and their hormone production. However, the role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function is largely unknown. Using thyroid follicular cell-specific insulin receptor (IR) and IGF-1 receptor (IGF-1R) double knockout (DTIRKO) mice, the coordinated role of IR and IGF-1R in thyroid development and function was evaluated in the thyroids of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. In contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced proliferation of thyroid follicular cells, which was mediated by the mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma. The results suggest that the availability of both IR and IGF-1R is a prerequisite for neonatal thyroid folliculogenesis. Our study provides novel insights into how crosstalk between IR/IGF-1R and TSH or ErbB signaling systems may underlie thyroid carcinogenesis.